Genetic engineering of non-human animals for the production of chimeric antibodies

Abstract

The invention provides non-human cells and mammals having a genome encoding chimeric antibodies and methods of producing transgenic cells and mammals. Certain aspects of the invention include chimeric antibodies, humanized antibodies, pharmaceutical compositions and kits. Certain aspects of the invention also relate to diagnostic and treatment methods using the antibodies of the invention.

The invention claimed is: 
     
       1. A mouse whose genome comprises a transgene, wherein the transgene comprises in operable linkage from 5′ to 3′ a gene segment encoding a human variable heavy (VH) polypeptide, a gene segment encoding a human diversity heavy (DH) polypeptide, a gene segment encoding a human joining heavy (JH) polypeptide, wherein the genome comprises a constant region gene comprising an exon encoding a rat CH1 polypeptide, an exon encoding a mouse CH2 polypeptide and an exon encoding a mouse CH3 polypeptide; wherein the constant region gene is operably linked with the gene segments encoding the VH, DH, and JH polypeptides. 
     
     
       2. The mouse according to  claim 1 , wherein the constant region gene further comprises an exon encoding a rat Cupper hinge polypeptide 3′ of the exon encoding a rat CH1 polypeptide and 5′ of the exon encoding a mouse CH2 polypeptide. 
     
     
       3. The mouse according to  claim 1 , wherein the transgene is capable of undergoing rearrangement and thereby upon expression produces a polypeptide comprising a human immunoglobulin heavy chain (IgH) variable region. 
     
     
       4. The mouse according to  claim 1 , wherein the constant region gene is on the transgene. 
     
     
       5. The mouse according to  claim 1 , wherein the transgene is randomly integrated. 
     
     
       6. The mouse according to  claim 1 , wherein the transgene is inserted into or adjacent to an endogenous IgH locus. 
     
     
       7. The mouse according to  claim 1 , wherein the transgene replaces all or a portion of an endogenous IgH locus. 
     
     
       8. The mouse according to  claim 1 , wherein all or a portion of an endogenous IgH locus of the mouse is functionally inactivated. 
     
     
       9. The mouse according to  claim 1 , wherein the genome further comprises a second transgene encoding an immunoglobulin (Ig) light chain, or a portion thereof, comprising a human light chain variable region. 
     
     
       10. The mouse according to  claim 9 , wherein the second transgene replaces all or a portion of an endogenous Ig light chain locus. 
     
     
       11. The mouse according to  claim 9 , wherein the Ig light chain is a human Ig light chain. 
     
     
       12. The mouse according to  claim 9 , wherein the Ig light chain, or portion thereof, comprises a human Igκ variable region. 
     
     
       13. The mouse according to  claim 12 , wherein the Ig light chain further comprises a human Igκ constant region. 
     
     
       14. The mouse according to  claim 9 , wherein the Ig light chain, or portion thereof, comprises a human Igλ variable region. 
     
     
       15. The mouse according to  claim 14 , wherein the Ig light chain comprises a human Igλ constant region. 
     
     
       16. The mouse according to  claim 15 , wherein the second transgene comprises an Igλ 3′LCR. 
     
     
       17. The mouse according to  claim 16 , wherein the Igλ 3′LCR is from a mammal selected from the group consisting of human, non-human primate, and rat. 
     
     
       18. The mouse according to  claim 15 , wherein second transgene comprises one or more human Vλ gene segments, 1 to 7 human Jλ gene segments, and a single human Cλ gene segment. 
     
     
       19. The mouse according to  claim 1 , wherein the constant region gene is on an additional transgene. 
     
     
       20. The mouse according to  claim 1 , wherein the constant region gene comprises an endogenous constant region exon.